Metformin is a commonly prescribed diabetes medication. Physicians have finally begun to prescribe it for polycystic ovarian syndrome (PCOS). It has side effects, just like any other medication; common side effects include diarrhea, nausea, vomiting, abdominal bloating, abdominal cramps or pain, flatulence, and anorexia 1,3, while lactic acidosis is rare but fatal. The literature on metformin-induced lactic acidosis reported these symptoms in patients with liver, kidney, or heart disorders, particularly in the acute form 7,8, but our patient had normal liver and kidney function prior to and during the study period.
Metformin raises lactate levels via a variety of mechanisms. In the intestine, it accelerates glycolysis and shifts glucose metabolism from aerobic to anaerobic pathways by modifying mitochondrial respiratory chain complex 1, particularly in hyperglycemic conditions. In the liver, it inhibits the hepatic redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, which reduces lactate uptake and suppresses gluconeogenesis in the liver. In other words, it impairs cellular energy production by inhibiting mitochondrial complex 1.
According to studies, 750mg of metformin per day neither impairs lactate elimination in the liver nor increases lactate production in the intestine to a level exceeding the ability of the normal liver to eliminate it 7–9. Our patient was taking 750 mg of metformin per day and had normal kidney function, so we ruled out the possibility of accumulated metformin in the body. We believe that the combined effects of metformin and GERD on the intestine cause high lactate levels that exceed the liver's ability to eliminate them (Fig. 1).
Metformin has shown promising results in the treatment of gastrointestinal disorders such as colitis 10, but most studies have been conducted on mice, and no studies have been conducted on GERD cases. In our case, our patient was managing GERD through lifestyle changes and had never needed a drug for it; however, after metformin administration, GERD symptoms grew increasingly intense; metformin progressed GERD from equilibrium to acute status. Metformin has a strong effect on the intestine, inhibiting stomach peristalsis, increasing pyloric contraction, and slowing gastric emptying by increasing the bile acid pool, inhibiting ileum absorption, and stimulating L-cell receptors to release glucagon-like peptide-1 (GLP-1). Furthermore, metformin affects the intestinal microbiota; some claim it increases the number of Escherichia coli and hydrogen production, causing bloating; and others claim it regulates short-chain fatty acid (SCFA)-producing bacteria, increasing the production of GLP1 and the gut hormone peptide YY (PYY) from the intestinal crypts, inhibiting gastric motility, and decreasing intestinal peristalsis. These effects of metformin on the intestine (Fig. 2) are known to worsen GERD symptoms 6,11.
One of the main factors causing GERD symptoms is stress 12. In our study, metformin exacerbated the patient's GERD after she began to feel stressed out about her weight gain. According to our research, metformin by itself may not be enough to cause GERD; nevertheless, stopping metformin and reducing stress did not make GERD symptoms go away. We propose that metformin alters the intestinal environment, rendering it vulnerable to GERD. More research is required to evaluate the long-term impact of metformin, particularly in patients who encounter intense side effects.
Metformin causes nausea and other gastrointestinal symptoms, which leads to weight loss; however, we noticed an increase in food intake in our patient. Moreover, metformin is well-known for its ability to reduce visceral fat. Surprisingly, our patient's visceral fat has increased by 3 kg. Studies suggested two mechanisms: the first was to reduce glucose absorption in the intestines while increasing its disposal in skeletal muscles, thereby depriving adipose tissue of glucose and decreasing adipose tissue mass; and the second was to decrease insulin sensitivity in the abdomen and increase it in the hepatic and skeletal muscles, thereby decreasing abdominal fat tissue 13. We propose that the opposite mechanism occurred in our patient 14,15.
Finally, It is noteworthy to note that exercise may cause lactate production when taken concurrently with metformin 7. Nevertheless, in our case, the patient had stopped exercising a year prior to starting metformin, and her only activity was walking, which does not promote anaerobic metabolism.
Unfortunately, we were limited in our ability to determine the precise mechanism underlying the development of lactic acidosis due to financial constraints and the unavailability of some tests, such as the metformin assay test (metformin level in plasma and erythrocytes). We did, however, perform kidney and liver function tests prior to metformin administration and followed them for a year after metformin was discontinued. Another limitation is the absence of electrolytes and blood arterial gas tests during metformin administration, which were only performed after she had stopped taking metformin for 6 months at 4:00 AM and had no symptoms; however, this gives us a hint that blood arterial gasses are either minimally or not affected at all. Despite these limitations, our study is the first to provide such a comprehensive analysis of multiple factors influencing metformin function, as well as to illustrate potential underlying mechanisms of metformin-induced lactic acidosis, acute GERD, and visceral fat.